Sodium hydride → ({2-Benzyloxycarbonylmethoxy-4-[2,7-difluoro-9-hydroxy-3,6-bis-(2-methoxyethoxymethoxy)-9H-xanthen-9-yl]-phenyl}-tert-butoxycarbonylmethyl-amino)-acetic acid tert-butyl ester

HRID 2357130Notes

Reaction equation

HRID 2357130 reaction equation
[C:1]([O:5][C:6](=[O:55])[CH2:7][N:8]([CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:45])[C:28]3[CH:27]=[C:26]([F:29])[C:25]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][C:18]([F:44])=[C:19]([O:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])[CH:20]=3)=[CH:11][C:10]=1[OH:46])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61]>CN(C=O)C>[C:51]([O:50][C:48](=[O:49])[CH2:47][N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:45])[C:28]3[CH:27]=[C:26]([F:29])[C:25]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][C:18]([F:44])=[C:19]([O:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])[CH:20]=3)=[CH:11][C:10]=1[O:46][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:55])([CH3:54])([CH3:53])[CH3:52]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 62576Benzyl bromoacetateHCID 68638322(tert-Butoxycarbonylmethyl-{4-[2,7-difluoro-9-hydroxy-3,6-bis-(2-methoxyethoxymethoxy)-9H-xanthen-9-yl]-2-hydroxy-phenyl}-amino)-acetic acid tert-butyl ester

Product 1

HCID 86596787({2-Benzyloxycarbonylmethoxy-4-[2,7-difluoro-9-hydroxy-3,6-bis-(2-methoxyethoxymethoxy)-9H-xanthen-9-yl]-phenyl}-tert-butoxycarbonylmethyl-amino)-acetic acid tert-butyl esterYield 76.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 15 (497 mg, 0.64 mmol) in DMF (10 mL) was treated with sodium hydride (18.5 mg, 0.77 mmol) at 0° C. under an Ar atmosphere. After stirring at 0° C. for 30 min, benzyl 2-bromoacetate (0.15 mL, 0.96 mmol) was added. The mixture was stirred at 0° C. for another 30 min and then warmed to room temperature overnight. The solvent was evaporated to dryness and extracted with EtOAc/H2O. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 40% EtOAc in Hexane (with 0.1% Et3N) to yield 453 mg (76%) of 16 as a light yellow oil. Rf=0.28 (in 40% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5H), 6.96 (d, 2H, J=7.2 Hz), 6.86 (d, 1H, J=8.4 Hz), 6.72 (dd, 1H, J=7.8 and 1.5 Hz), 6.59 (m, 3H), 5.28 (s, 4H), 5.15 (s, 2H), 4.89 (s, 1H), 4.64 (s, 2H), 4.01 (s, 4H), 3.86 (m, 4H), 3.58 (m, 4H), 3.39 (s, 6H), 1.39 (s, 18H); 13C NMR (75 MHz, CDCl3) 6170.3, 168.8, 150.7, 149.9, 147.5, 146.6, 146.5, 144.4, 144.3, 139.1, 138.9, 135.3, 128.6, 128.4, 128.3, 122.9, 120.0, 117.0, 116.9, 116.2, 116.1, 115.8, 105.9, 94.7, 81.2, 71.5, 68.1, 66.7, 66.6, 59.0, 54.5, 42.6, 28.0; 19F NMR (282 MHz, CDCl3) δ −140.2 (dd, 2 F); mass spectrum, calculated for C46H55F2NO13 (M−17) 909.4, Found 910.1.

Workup

  1. stirringThe mixture was stirred at 0° C. for another 30 min
  2. temperaturewarmed to room temperature overnight
  3. customThe solvent was evaporated to dryness
  4. extractionextracted with EtOAc/H2O
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by flash column chromatography
  9. washeluting with 40% EtOAc in Hexane (with 0.1% Et3N)

Sources & evidence

ORD record
ord-a0ffefacd3544c79b0d3a2bd40e15042
Source dataset
uspto-grants-2010_07
Patent number
US07759459B2

Reaction notes

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